Association Between Single Nucleotide Polymorphisms in the Cyclooxygenase-2, Tumor Necrosis Factor-α, and Vascular Endothelial Growth Factor-A Genes, and Susceptibility to Hepatocellular Carcinoma

Abstract

Cyclooxygenase-2 (COX-2), vascular endothelial growth factor-A (VEGF-A), and tumor necrosis factor-α (TNF-α) are mediators of inflammation and angiogenesis; all of them are produced in liver cirrhosis (LC) and in hepatocellular carcinoma (HCC). It was proposed that there is an association between single nucleotide polymorphisms (SNPs) and HCC. These allelic variants influence the transcriptional activity of these genes, and therefore the proteins levels. The VEGF-A pathway is a potential therapeutic target in HCC, and several antiangiogenic agents have entered clinical trials in HCC. We evaluated the frequency of SNPs of COX-2, TNF-α, and VEGF-A genes in patients with HCC versus LC patients and a control group. The aim of this article was to verify the correlation between the allelic variations and the risk of developing HCC. The study included 96 HCC, 79 LC patients, and 162 healthy subjects. The evaluation of SNPs was performed by the restriction fragment length polymorphism (RFLP-PCR) method. The SNPs analyzed were: -1195 G>A of the COX-2 gene, -308 G>A of the TNF-α gene, and +936 C>T of the VEGF-A gene. Chi-square and Fisher exact tests were used for statistical analysis. Our results confirm that carriers with the C allele in the VEGF-A gene are more frequent in HCC versus LC (p=0.039), suggesting that this SNP may predispose to the development of HCC.

A randomised controlled trial of meloxicam, a Cox-2 inhibitor, to prevent hepatocellular carcinoma recurrence after initial curative treatment

“…Furthermore, Cox-2 is revealed to mediate the regulation of cell growth, motility, adhesion, and apoptotic suppression [14]. Increased expression of Cox-2 promotes tumor proliferation, and inhibition of the Cox-2 pathway suppresses carcinogenesis, suggesting Cox-2 may contribute to the development of cancer [20]. …”

Influence of vascular endothelial growth factor and alpha-fetoprotein on hepatocellular carcinoma

“…An association between the mutant genotype (TT) of VEGF -C936T with nodal invasion for HCC has also been found, which is an indicator of poor disease prognosis (Kong et al, 2007). However, another study found that the carriers of the CC genotype are more susceptible to HCC development (Giacalone et al, 2011). It is possible that the profile of this series, including the recognized miscegenation of the Brazilian population (Lopes Maciel et al, 2011) and the small number of individuals studied have influenced this analysis.…”

HapMap-based study of CIP2A gene polymorphisms and HCC susceptibility

“…First, the hypothesis-directed approach is used to investigate func- tional SNPs in coding regions since they may dysregulate the expression of proteins (12)(13)(14)(15). Second, the indirect approach is used to select a set of htSNPs which are informative polymorphisms that best characterize the haplotype diversity of a given chromosomal region.…”

“…Chronic infections of hepatitis B virus (HBV) and hepatitis C virus (HCV), excessive alcohol consumption, tobacco smoking, aflatoxin B1 (AFB1) and diabetes are reported to be associated with an increased risk of HCC (4)(5)(6)(7)(8)(9)(10). Among these known or suspected risk factors, single nucleotide polymorphisms (SNPs) may also play a significant role in infectious and non-infectious pathways associated with HCC (11)(12)(13)(14). SNPs of oncogenes and anti-oncogenes may alter the gene expression level and are functionally associated with HCC and other forms of liver disease (15).…”